Institute for Cancer Genetics, Columbia University, New York, NY, USA.
Department of Systems Biology, Columbia University, New York, NY, USA.
Nat Cancer. 2020 Nov;1(11):1113-1127. doi: 10.1038/s43018-020-00124-1. Epub 2020 Oct 19.
Multi-agent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene-drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identifies common and drug-specific pathways modulating chemotherapy response and underscores the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open novel therapeutic opportunities for the treatment of relapse and refractory disease.
多药物联合化疗可治愈急性淋巴细胞白血病 (ALL)。然而，原发性难治性疾病或复发性白血病患者的预后非常差。在这里，我们综合深入分析了诊断和复发的儿科及成人 ALL 样本的突变景观，并对七种 ALL 化疗药物的基因-药物相互作用进行了全基因组 CRISPR 筛选分析。通过结合这些分析，我们揭示了诊断和复发特异性的突变机制以及化疗耐药的遗传驱动因素。从功能上看，我们的数据确定了调节化疗反应的常见和药物特异性途径，并强调了药物组合在限制耐药性遗传病变选择方面的作用。此外，通过鉴定逆转化疗耐药的可行靶点，这些分析为治疗复发和难治性疾病开辟了新的治疗机会。
